Substituted 3-(2-naphthyl)-cyclohexane



Patented Aug. 24, 1954 SUBSTITUTED 3- Z-NAPHTHYL) CYCLOHEXANE FrederickC. Novello, Lansdale, Pa.. assignor to Merck & 00., Inc., a corporationof New Jersey No Drawing. Application January 28, 1952, SerialNo.268,693

6 Claims. 1

This invention relates to novel chemical compounds, and in particular tonovel 2,6-disubstituted naphthalene compounds which can be illustratedby the general formula wherein either (a) there is no unsaturationbetween the 2- and 3-position carbon atoms of the cyclohexyl radical, or(b) there is a double bond linkage between the carbon atoms in the 2-and 3-positions; and wherein R is hydrogen or an alkyl group, preferablya low molecular weight alkyl group; and A is an aliphatic radical havingthe structure or a radical convertible thereto, such as the carbonylradical having the structure These compounds are useful as intermediatesin the synthesis of steroid hormones. In addition, some of the newcompounds have been found to have estrogenic activity, while others havebeen found to be useful in the treatment of collagen diseases.

The compounds of the invention are advantageously prepared fromZ-(beta-dialkylaminopropionyl)-6-alkoxynaphthalene which is made fromthe readily obtainable 2-'(lower aliphatic acyl)-6-alkoxynaphthalenes,an acid additions salt of a dialkylamine, and paraformaldehyde. Uponheating these intermediates, suitably under reflux, the acid additionsalt of a Z-(beta-dialkylaminopropionyl)-6-all oxynaphthalene isobtained, which, upon heating with an alkyl ester of acetoacetic acid,preferably a lower-alkyl ester of acetoacetic acid, such as the methylorethylacetoacetate, advantageously in the presence of an alkali metal, assodium or potassium, dissolved in a primary-, secondary-, ortertiary-alcohol, advantageously potassium dissolved in tertiarybutylalcohol, or sodium hydroxide or potassium hydroxide in alcohol, isconverted to 8- (fi-alkoxy- 2-naphthyl) cyclohexen-2-one-l. Thiscompound can then be converted into any of the other compounds embracedwithin the scope of the above general formula. Thus, by hydrogenation inthe presence of palladium, one molar alkoxide.

equivalent of hydrogen is absorbed and the compound is converted to thecorresponding 3-(6- alkoxy-2-naphthyl)-cyclohexanone; or if thehydrogenation is conducted in the presence of platinum, two molecularequivalents of hydrogen can be introduced into the molecule convertingit to the corresponding 3- (G-alkoxy-Z-naphthyl) cyclohexanol-l.Likewise, if the saturated carbonyl compound, obtained as the result ofhydrogenation in the presence of palladium, is treated with anadditional molecular equivalent of hydrogen in the presence of platinum,the same 3-(6-alkoxy-2-naphthyl) -cyclohexanol-1 is obtained. The 3-6-alkoxy-2-naphthyl) -cyclo hexen-Z-o-ne-l can also be converted to3-(6- alkoxy-2-naphthyl)-cyclohexen-2-ol-1 by heating it, suitably undera reflux condenser, and advantageously in the presence of an excess ofan aluminum alkoxide, such as aluminum isopropoxide, whilesimultaneously removing by distillation the acetone formed during thereaction.

Similarly, the 3- (fi-alkoxy-z-naphthyl)-cyclohexen-Z-one-l can beconverted to the 6-hydroxy-2-naphthyl derivatives by heating thecarbonyl compound, advantageously under reflux conditions in thepresence of an inert solvent and a catalyst, such as an aluminum halide,preferably the chloride or bromide. The 3- (G-hydroxy-2-naphthyl)-cyclohexen-2-one-l can be treated in the same manner as theproduct from which it was obtained to convert it to the corresponding-6-hydroxy-2-naphthyl derivatives, such as the 3- (6-hydroxy- 2-naphthyl)-cyclohexanone by hydrogenation in the presence of palladium; the3-(6-hydroxy-2-naphthyl)-cyclohexanol by hydrogenation in the presenceof platinum; the 3- I (6 n hydroxy 2 naphthyl) cyclohexen 2 ol-l byheating in the presence of an aluminum The 3- (d-hydroxy-Z-nap-hthyl)-cyclohexen-2-one-l can also be converted to the desirable3-(6-hydroxy-5,6,7,8tetrahydro-2-naphthyl)-cyclohexanol by hydrogenationat elevated temperatures and pressures in the presence of alcoholicalkali and a nickel catalyst; and the 3- 6-hydroxy-2-naphthyl)-cyclohexanone can be converted to 3-(6-hydroxy-2-naphthyl)-cyc1ohexanolby hydrogenation in the presence of platinum.

The preparation of the various compounds of this invention is explainedin more detail by the following illustrative examples. It is to beunderstood, of course, that many modifications can be made in thereaction conditions, and itis not intended that the invention be limitedto the explicit reaction conditions recited in the .examples.

1.3- (G-methczcy-Z-naphthyl) -cycloheren-Z-one-I Example gave 2-(beta-dimethylaminopropionyl) -6-methoxynaphthalene hydrochloride, M. P.184-1855 C was mixed with 25.2 grams of methyl acetoacetate and refluxedfor 24 hours with a solution.

(17) Sixty grams of the above obtained product .the same proceduredescribed in Example 6,

of 10.0 grams of potassium in 850 ml. of ter-' tiary-butyl alcohol. Themixture was then cooled, acidified with dilute hydrochloric acid andfiltered. The filtrate was concentrated in vacuo and the residue treatedwith 500 ml. of water and cooled in an ice bath. The solid was collectedon the filter and dissolved in benzene. The'benzene solution was thenwashed with two 100 ml. portions of water, two 100 ml. portions of 5%sodium hydroxide, two 100 ml. portions of water and then dried oversodium sulfate, filtered and evaporated to dryness. Crystallization froma mixture of acetone-petroleum ether yielded 3 (6-methoxy-2-naphthyl)-cyclohexen- 2-one-1, M. P. 1423-1433 C.

Example 2.3- (6-ethomy-2-naphthyl) -cyclohemen-Z-one-L-By replacing the2-acetyl-6- methoxynaphthalene of Example 1 by an equimolecular quantityof Z-acetyl-G-ethoxynaphthalene and following substantially the sameprocedure described therein, there is obtained 3-(6- ethoXy-Zmaphthyl)-cyclohexen-2-one-l.

Example 3.3- (ti-propory-Z-naphthyl) -cycloheaen-2-one-1.By replacingthe 2-acetyl-6- methoxynaphthalene of Example 1 by an equimolecularquantity of 2-acetyl-6-propoxynaphthalene and following substantiallythe same procedure described therein, there is obtained 3-(6-propoxy-2-naphthyl) -cyclohexen-2-one-l.

Example 4.3-(ti-butomy-Z-naphthyl)-cyclo- Iiexen-2-one-1.-By replacingthe 2-acetyl-6- methoxynaphthalene of Example 1 by anequimol'ecularquantity of 2-acetyl-6-butoxynaphthalene and followingsubstantially the same procedure described therein, there is obtained 3-(6- butoxy-Z-naphthyl)-cyclohexen-2-one-1.

Example 5 .-3( 6-pentomy-2-naphthyl) -cycloheaen-Z-one-L-By replacingthe 2-acetyl-6- methoxynaphthalene of Example 1 by an equimolecularquantity of 2-acetyl-6-pentoxynaphthalene and following substantiallythe same procedure described therein, there is obtained 3-(6-pentoxy-2-naphthyl) -cyclohexen-2-one- 1 Example 6.3-(ii-methory-Z-naphthyl) -cycloheaanone-A solution of 5.0 grams of 3-(ii-methoxy-2-naphthyl)-cyclohexen-2-one-1, obtained as in Example 1, in50 ml. of dioxane was shaken with hydrogen at atmospheric pressure at5055 C. in the presence of 1 gram 5% palladium charcoal catalyst untilone molar equivalent of hydrogen was absorbed. The solution wasfiltered, concentrated, and the product crystallized from alcoholyielding 3 (6 methoxy 2 naphthyl) cyclohexanone, M. P. 124-125 C.

Example 7 .3- (d-ethoacy-Z-naphthyl) -cg, clohemanone.By replacing the3-(6-inethoxy-2- naphthyl)-cyclohexen2-one-1 of Example 6 by anequimolecular quantity of 3- (6-ethoxy-2- naphthyl)-cyclohexen-2-one-1,prepared as de- 4 scribed in Example 2, and following substantially thesame procedure described in Example 6, there is obtained 3-(6-ethoxy-2-naphthyl) -cyclohexanone.

Example 8.-3- (G-butozcy-Z-naphthyl) -cyclohemanone.-By replacing the 3-(6-methoxy-2- naphthyl)-cyclohexen-2'-one-I of Example 6 by anequimolecular quantity of 3-(6-butoxy-2- naphthyl)-cyclohexen-2-one-1,prepared as described in Example 4, and following substantially there isobtained 3- (6-butoxy-2-naphthyl) -cyclohexanone.

Example 9.3 (6-methoay-2-naphthyl) -cyclohexanol.A solution of 1 gram of3-(6-methoxy-2-naphthyl)-cyclohexen-2-one-l, obtained asdescribed inExample 1, in 50 m1. of ethanol was shaken with hydrogen at atmosphericpressure in the presence of 150 mg. of platinum catalyst until 2 molarequivalents of hydrogen were absorbed. The solution was filtered,concentrated, and the product crystallized from a mixture ofalcohol-hexane, yielding 3-(6-methoxy- 2-naphthyl)-cyclohexanol, M. P.127.6-1292" 0.

Example 10.3- (G-ethoay-Z-naphthyl) -cycloheatmoL-By replacing the3-(6-methoxy-2- naphthyl)-cyclohexen-2one-1 of Example 9 by anequimolecular quantity of 3-(6-ethoxy-2- naphthyl)-cyclohexen-2-one-l,prepared as described in Example 2, and following substantially the sameprocedure described in Example 9, there is obtained3-(6-ethoxy-2-naphthyl) -cyclohexanol.

Example 11 .3-(d-methoxy-Z-naphthyl) -cycloheasanol.l gram of3-(6-methoxy-2maphthyD-cyclohexanone, obtained as described in Example6, was dissolved in 50 ml. ethanol and shaken with hydrogen at roomtemperature and at atmospheric pressure in the presence of. milligramsof Adams catalyst until a molar equivalent of hydrogen had beenabsorbed. The solution was then filtered to separate the catalyst, thefiltrate concentrated and the 3-(6- methoxy-2-naphthyl)-cyclohexanolcrystallized from a mixture of alcoholhexane, M. P. 127.6- l29.2 C.

Example 12.3 (6-ethoary-2-naphthyl) -cyclohemanol.l 3y replacing the 3(6 methoxy-Z- naphthyD-cyclohexanone of Example 11 by an equimolecularquantity of 3-(6-ethoxy-2-naphthyll-cyclohexanone, prepared as describedin Example '7, and following substantially the same procedure describedin Example 11, there is obtained 3- (6-ethoxy-2-naphthyl) -cycl0hexanol.

Example 13.--3 (6 methozry 2 naphthyl) cyclohexen-2-ol-1.1.26 grams of3-(6-methoxy- Z-naphthyl) -cyclohexen-2-one-1, obtained by the processdescribed in Example 1, was dissolved in a mixture of 20 ml. of drybenzene and 25 ml. isopropanol and refluxed with excess aluminumisopropoxide in such a manner that acetone, which is a product of thereaction, was distilled dropwise from the reaction mixture. When no moreacetone came over, the reaction mixture was hydrolyzed with dilutesulfuric acid and the white precipitate was collected on a filter andwashed with water. Crystallization from a mixture of alcohol-wateryielded 3-(6-methoXy-2- naphthyl) cyclohexen-2-ol- 1.

Example 14.3- (G-DutOmy-Z-naphthyZ) -cyclohexen-2-oZ-1.By replacing the3- (ti-methoxy-Z- naphthyl)-cyclohexen-2-onel of Example 13 by anequimolecular quantity of 3-(6-butoxy-2- naphthyl)-cyclohexen-2-one-l,prepared by the process described in Example 4, and followingsubstantially the same procedure described in Example 13, there isobtained 3-(6 -butoxy-2- naphthyl) cyclohexen-2-ol-1.

Example 15.3 (6 hydroscy 2 naphthyl) cycloheren-2-one-1.A solution of2.5 grams of 3 (6-rnethoxy-2-naphthyl) -cyclohexen-2-one-1, prepared bythe process described in Example 1, in 40 ml. xylene was refluxed for 15minutes with 5 grams of aluminum chloride. The reaction mixture was thencooled and poured onto a mixture of 25 grams of ice and ml. ofconcentrated hydrochloric acid. The solid precipitate was collected on afilter, dissolved in hot 10% aqueous sodium hydroxide, decolorized andacidified while hot with hydrochloric acid yielding 3- (-fi-hydroxy-2-naphthyl)cyclohexen-Z-one-l, which, after recrystallization from amixture of alcohol-hexane, melted at 215.1-217.4 C.

Any 3 (6 alkoxy-Z-naphthyl)-cyclohexen-2- one-1, such as any of thecompounds prepared by the process described in Examples 2through 5 ortheir chemical equivalents, can be hydrolyzed in substantially the samemanner outlined in Example to produce 3-(6-hydroxy-2-naphthyD-cyclohexen-2-one-1.

Example 16.-3-(6-hydro:cy 2 naphthyl) -011- cloheasanona-A solution of 1gram 3-(6-hydroXy-Z-naphthyl)-cyclohexen-2-one-1, as prepared in Example15, in 70 ml. of glacial acetic acid was shaken with hydrogen atatmospheric pressure in the presence of 150 mg. of palladium catalystuntil one molar equivalent of hydrogen was absorbed. The solution wasthen filtered, concentrated to dryness in vacuo and the product purifiedby distillation at 0.5 mm. followed by crystallization from a mixture ofbenzene-hexane, yielding 3-(6-hydroxy-2-naphthyl)-cyclohexanone meltingat 147150 C.

Example 17.3(6-hydroxy 2 naphthyl) -cyclohemanol.A solution of 1 gram of3-(6-hydroxy-2-naphthyl) -cyclohexen 2 one-1, prepared by the processdescribed in Example 15, in 100 ml. of ethanol was shaken with hydrogenat atmospheric pressure in the presence of 1 gram of nickel catalystuntil hydrogen absorption ceased. The solution was filtered andconcentrated in vacuo and'the residue taken up in 150 ml. of ether. Theethereal solution was washed with water, then with 5% sodium bicarbonatesolution and then dried over anhydrous sodium sulfate, filtered andevaporated to dryness. After crystallization from a mixture ofalcohol-water, the product, 3-(6-hydroxy-2- naphthyl)-cyclohexanolmelted at 217-218 C.

Example 18.--3-(6-hydroxy 2 naphthyl) -cyclohexanoL-One gram of3-(6-hydroxy-2- naphthyl) -cyclohexanone, prepared as in Example 16, in50 ml. ethanol was shaken with hydrogen at room temperature and atatmospheric pressure in the presence of 100 mgms. of platinum catalyst.After the theoretical quantity of hydrogen for the reduction of ketoneto carbinol had been absorbed, the solution was filtered from thecatalyst, concentrated and the product crystallized from a mixture ofalcohol-water yielding 3-(6-hydroxy-2-naphthyl)-cyclohexanol, M. P.217-218 C.

Example 19.-3-(6-hydro.ry 2 naphthyl) -c'J- clohezcen-Z-ol-L-A solutionof 2.4 grams of 3-(6 hydroxy 2 naphthyl) cyclohexen-2- one-1, preparedas in Example 15, in cc. of water containing 606 mgms. sodium hydroxidewas shaken with 1.3 grams of acetic anhydride. The solid material thusformed was collected on a filter, washed with water and crystallizedfrom a mixture of alcohol-water yielding 3-(6-acetoxy-Z-naphthyl)-cyclohexen-2-one-1. Treatment of this product'with aluminumisopropoxide in the manner described in Example 13 yielded 3-(6-acetoxy-2-naphthyl) cyclohexen-Z-ol-l. Brief refluxing in the presenceof dilute alcoholic alkali yielded 3- (6-hydroxy-2-naphthyl)-cyclohexen-2- ol-l.

Example 20.-3- (G-hydromy-5,6,7,8-tetrahydro-Z-naphthyl)-cyclohe:canol.-A mixture of 2 grams of3-(6-hydroxy-2-naphthyl) -cyclohexen- 2-one-1, prepared as in Example15, 300 mg. of nickel catalyst, 20 mg. sodium hydroxide and 50 ml.alcohol was shaken in an autoclave with hydrogen under pressure (2,000lbs. per sq. inch) at C. for five hours. When cool, the autoclave wasopened and the contents washed with alcohol into a beaker. The solutionwas evaporated to dryness and the residue taken up in ml. of ether. Theethereal solution was washed with water, dilute sodium hydroxidesolution, and then water, dried over sodium sulfate, filtered andevaporated to dryness. 3-(6- hydroxy-5,6,'7,8-tetrahydro 2 naphthyl)-cyclohexanol was obtained as an oily product upon distillation of theresidue in high vacuum.

What is claimed is:

1. A 2,6-disubstituted naphthalene compound selected from the class ofcompounds having the general formulae wherein R is selected from theclass consisting of hydrogen and a lower alkyl radical; and A isselected from the class consisting of H /OH and I o H o radicals.

2. 3- (6-hydroxy-2-naphthyl) -cyclohexanone. 3. 3-(6-methoxy-2-naphthyl) -cyclohexanone. 4. 3-(6-methoxy 2 naphthyl)-cyclohexen-2- one-l.

5. 3-(6-hydroxy 2 naphthyl) -cyclohexen-2- on -1.

6. 3-(6-hydroxy 567,8 tetrahydro-2-naphthyl) -cyclohexanol.

References Cited in the file of this patent UNITED STATES PATENTS NumberName Date 2,364,056 Bruson Dec. 5, 1944 FOREIGN PATENTS Number CountryDate 514,592 Great Britain Nov. 13, 1939 OTHER REFERENCES Woods et a1.,Jour. Am. Chem. Soc., vol 73, 1951, pp. 3854-56.

1. A 2.6-DISUBSTITUTED NAPHTHALENE COMPOUND SELECTED FROM THE CLASS OFCOMPOUDS HAVING THE GENERAL FORMULAE